A systematic investigation of the maximum tolerated dose of cytotoxic chemotherapy with and without supportive care in mice

BMC Cancer

Research Article

Richard A. Lake¹  W. Joost Lesterhuis¹  Danika E. Hope¹  Bruce W. Robinson¹  Wayne J. Aston¹  Anna K. Nowak² 

[1] National Centre for Asbestos Related Diseases, University of Western Australia, 5th Floor, QQ Block, 6 Verdun Street, 6009, Nedlands, WA, Australia;Faculty of Health and Medical Science, The University of Western Australia, 35 Stirling Highway, 6009, Crawley, WA, Australia;National Centre for Asbestos Related Diseases, University of Western Australia, 5th Floor, QQ Block, 6 Verdun Street, 6009, Nedlands, WA, Australia;Faculty of Health and Medical Science, The University of Western Australia, 35 Stirling Highway, 6009, Crawley, WA, Australia;Department of Medical Oncology, Sir Charles Gairdner Hospital, 6009, Nedlands, WA, Australia;

关键词: Chemotherapy;    Mice;    Dose optimization;    Maximum tolerated dose;    MTD;    Supportive care;    Cancer;   

DOI  :  10.1186/s12885-017-3677-7

 received in 2016-12-07, accepted in 2017-10-08,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundCytotoxic chemotherapeutics form the cornerstone of systemic treatment of many cancers. Patients are dosed at maximum tolerated dose (MTD), which is carefully determined in phase I studies. In contrast, in murine studies, dosages are often based on customary practice or small pilot studies, which often are not well documented. Consequently, research groups need to replicate experiments, resulting in an excess use of animals and highly variable dosages across the literature. In addition, while patients often receive supportive treatments in order to allow dose escalation, mice do not. These issues could affect experimental results and hence clinical translation.MethodsTo address this, we determined the single-dose MTD in BALB/c and C57BL/6 mice for a range of chemotherapeutics covering the canonical classes, with clinical score and weight as endpoints.ResultsWe found that there was some variation in MTDs between strains and the tolerability of repeated cycles of chemotherapy at MTD was drug-dependent. We also demonstrate that dexamethasone reduces chemotherapy-induced weight loss in mice.ConclusionThese data form a resource for future studies using chemotherapy in mice, increasing comparability between studies, reducing the number of mice needed for dose optimisation experiments and potentially improving translation to the clinic.

【 授权许可】

CC BY   
© The Author(s). 2017